This invention is in the field of medical devices, specifically defoaming components for extracorporeal blood processing devices such as oxygenators and cardiotomy reservoirs.
Blood processing apparatus including oxygenators, cardiotomy reservoirs and defoamers, blood filters, autotransfusion devices, drip chambers, and other devices through which blood is moved, e.g., by pumping, often require agitation such that air is mixed with blood, causing foaming. This foam must be removed before the blood is put into the patient""s circulatory system.
Many surfactants are used as industrial antifoaming agents including selected block copolymer polyol surfactants, polyether block copolymers, polyoxyethylene sorbitan esters and silicone-based surfactants. These surfactants are generally used as defoamers by mixing them into the liquid to be defoamed.
TWEEN 80(trademark) (ICI Specialty Chemicals, see ICI product literature) is a well-known industrial and biological surfactant which is a polyoxyethylene sorbitan ester. TWEEN 80(trademark) has been used as a debubbling agent in blood-containing medical devices.
Block copolymer polyol surfactants composed of ethylene oxide and propylene oxide are used as defoamers and antifoamers in a wide variety of applications such as industrial processing, latex paints, cleaning, water treatment and fermentation. Currently two groups of polyol surfactants are commercially available. These are PLURONIC(trademark), PLURONIC-R(trademark), TETRONIC(trademark), TETRONIC-R(trademark) and PLUROFAC(trademark) surfactants (BASF product literature 1989). Polyols with various structures and molecular lengths can be synthesized by altering the reaction sequences and degree of polymerization with or without adding ethylenediamine coupling agent. Block copolymers composed of ethylene oxide are hydrophilic while those composed of propylene oxide are hydrophobic. These polyol surfactants have not been known to be applied as defoamers/antifoamers in blood-contacting medical devices especially for use in extracorporeal circulation.
ANTIFOAM A(trademark), Dow Corning Corporation, Midland, Mich. (Dow Corning Product Literature, 1985), a polydimethylsiloxane surfactant, has been used as an antifoaming agent for blood processing devices. Dow Coming also manufactures a similar polydimethylsiloxane defoaming agent sold under the trademark SIMETHICONE(trademark) which may be used in blood processing devices. ANTIFOAM A(trademark) is coated on blood-contact surfaces of such devices to prevent foaming. Device surfaces are usually coated by dipping them in a solution of ANTIFOAM A(trademark) in a halogenated hydrocarbon. Generally, defoaming units of blood processing devices provide a very large surface area which is covered by the defoaming agent. The surface area is usually composed of a synthetic material such as polyurethane foam, polypropylene mesh, polyvinylchloride strips or stainless steel wool. Other surfactants containing silicone which are water-soluble are also known to the art including those of GE Silicone Division, Waterford, N.Y. such as SM-70.
Silicone-containing surfactants used in blood processing devices, specifically, ANTIFOAM A(trademark), have recently been implicated in the formation of emboli in patients who died after cardiopulmonary bypass surgery. (J. M. Orenstein, et al. (1982), xe2x80x9cMicroemboli Observed in Deaths Following Cardiopulmonary Bypass Surgery,xe2x80x9d Human Pathology 13:1082-1090.) ANTIFOAM A(trademark), as a hydrophobic surfactant, has the further disadvantage of retarding liquids in the defoaming unit of oxygenating instruments, thus unnecessarily impeding blood flow through the unit.
To avoid problems of blood interaction with the blood-contact surfaces which may cause trauma to the blood, the use of defoaming agents has been described in combination with heparin in blood processing devices. (L-C. Hsu, et al., xe2x80x9cThrombo-resistant Coating for Defoaming Applications,xe2x80x9d PCT Publication WO 92/21387.) Defoaming agents are described as comprised of both active compounds and carriers, occasionally including a spreading agent. Typical active compounds listed include fatty acid amides, higher molecular weight polyglycols, fatty acid esters, fatty acid ester amides, polyalkene glycols, organophosphates, metallic soaps of fatty acids, silicone oils, hydrophobic silica, organic polymers, saturated and unsaturated fatty acids, and higher alcohols. Typical carriers include paraffinic, naphthenic, aromatic, chlorinated, or oxygenated organic solvents. ANTIFOAM A(trademark) dissolved in a mixture of FREON (DuPont Co.) and methylene chloride in combination with heparin is a preferred antifoaming composition in this patent application for avoiding problems of blood interaction with blood-contact surfaces.
Nogawa, et al. U.S. Pat. No. 5,162,102 describes the use of nonionic surface-active agents which are polyethers consisting of block copolymers of propylene oxide and ethylene oxide (i.e., PLURONIC(trademark) and TETRONIC(trademark) surfactants), to coat blood-contacting surfaces of medical devices for debubbling purposes. In that patent a debubbling agent is used to coat the hydrophobic blood-contact surfaces so that air can be removed from the system during a priming operation prior to blood circulation, leaving few bubbles adhered to the surfaces, as the patent teaches that during blood circulation, such bubbles gradually enter the blood, causing blood foaming. The surfactant may be used by coating on the inside of the housing. Then when the priming liquid is passed into the system, the surfactant dissolves and is distributed over the entirety of the blood-contact surfaces, and renders them more hydrophilic. In the preferred embodiment disclosed in this patent, a xe2x80x9cdebubblerxe2x80x9d or defoaming unit to remove bubbles from blood is described. This defoaming unit (such as a urethane, cellulose, or nylon foam), works to remove bubbles from blood by allowing bubbles to grow by virtue of its hydrophobic nature. Thus, this patent teaches away from the use of a surfactant durably deposited onto the blood-contact surfaces, particularly onto defoamer surfaces, as such would interfere with the function of the defoamer described in said patent. The PLURONIC F68 debubbling composition disclosed in U.S. Pat. No. 5,162,102 is not suitable as a defoaming composition as defined herein. As set forth in the BASF product literature (1989), page 13, F68 is a water-soluble surfactant that produces foam and should only be used in applications where foam production is desirable.
A number of water soluble PLURONIC(trademark) or TETRONIC(trademark) surfactants have been found to produce fair to excellent results when used in combination with buffers and osmolality fillers as debubbling agents for sheath streams in biomedical analytical systems. These are PLURONIC P85(trademark), P84, P105, P87 and TETRONIC 908(trademark). European Patent Publication 0 214 614 published Mar. 18, 1987, for xe2x80x9cNon-Lytic Sheath Composition.xe2x80x9d The water solubility of these surfactants at operating temperatures would preclude their use in defoaming applications where durable retention on a hydrophobic surface is desired.
The nonbiotoxic nature of polyol surfactants was known about thirty years ago. Generally the polyols have low acute oral and dermal toxicity and low potential for causing irritation or sensitization. The typical oral LD50(trademark) is greater than 10 grams per kilogram and dermal LD50(trademark) is greater than five grams per kilogram. In medical applications, the PLURONIC F68(trademark) polyol has been extensively studied. Adding F68 to blood to minimize fat globulemia during cardiopulmonary bypass surgery was corroborated on clinical patients. (E. S. Wright et al. (1963), Fat Globulemia in Extracorporeal Circulation,xe2x80x9cSurgery 53:500-504; and Y. Miyauchi et al. (1966),xe2x80x9cAdjunctive Use of a Surface-Active Agent in Extracorporeal Circulation,xe2x80x9d Supplement I to Circulation, 33 and 34, I-71-1-77.) Concentrations less than five percent F68 were shown to protect erythrocytes against osmotic hemolysis. (C. Roze (1966), xe2x80x9cOsmotic Behavior of Erythrocytes in Solutions of a Non-ionic Detergent: Pluronic F-68,xe2x80x9d C.R. Acad. Sci. 263:1615-1618.) The use of F68 as a blood plasma expander in heart-lung bypass has been suggested. (A. C. Hymes and P. Baute (1964), xe2x80x9cPluronics: First Use as a Plasma Expander,xe2x80x9d Supplement II to Circulation 35 and 36, II-148; A. C. Hymes et al. (1968), xe2x80x9cA comparison of Pluronic F-68, low molecular weight dextran, mannitol, and saline as priming agents in the heart-lung apparatus,xe2x80x9d J. Thoracic and Cardiovas. Surg. 56:16-22.)
Other workers have looked at the biocompatibility of PLURONIC(trademark) surfactants. Lee, et al. (1989), xe2x80x9cProtein-resistant Surfaces Prepared by PEO-containing Block Copolymer Surfactants,xe2x80x9d J. Biomedical Material Research 23:351-368, incorporated herein by reference, discloses the coating of low density polyethylene film with polyethylene oxide (PEO) and polybutylene oxide (PBO) block copolymers including PLURONIC L64(trademark) (BASF), SYNPERONIC PE-L64C(trademark) (ICI), TETRONIC 1504(trademark) (BASF) and BUTRONIC 184(trademark) (BASF). Adsorption of the block copolymers on the surface depended on the molecular structure of the copolymers and protein resistance was dependent on the amount of copolymer adsorbed and on PEO chain mobility.
M. Amjii and K. Park (1992), xe2x80x9cPrevention of Protein Adsorption and Platelet Adhesion on Surfaces by PEO/PPO/PEO Triblock Copolymers,xe2x80x9d Biomaterial 13:682-692, incorporated herein by reference, discloses that the ability of PLURONIC(trademark) to prevent platelet adhesion was mainly dependent on the number of propylene oxide residues (rather than the number of ethylene oxide residues). The number of propylene oxide residues in the copolymer is also linked to the tightness of binding to a hydrophobic substrate. PLURONIC(trademark) surfactants tested included L63, L64, P65, F68, P103, P104, P105 and P105. PLURONIC P103(trademark) and P108 were said to be effective in repelling fibrinogen and platelets from surfaces. As long as the surfactant is tightly bound to the surface, which binding is determined by the number of propylene oxide residues, then the PEO moieties can effectively block fibrinogen adsorption and platelet adhesion by steric repulsion.
To solve the problems of embolus formation, blood interaction with blood-contact surfaces, retention of fluid in defoaming units, and the environmentally unsafe use of halogenated hydrocarbons as solvents, it is desirable to provide an antifoaming composition which is biocompatible, long-lasting when coated on the blood-contact surfaces, i.e. does not wash off into the blood, and which may be solubilized in an alcohol or nonhalogenated hydrocarbon solvents.